Abstract 6072: Chromosomal aneuploidy, whole-genome doubling and mutational signatures in NCI PDMR models
Authors: Li Chen, Biswajit Das, Ting-Chia Chang, Yvonne A. Evrard, Chris A. Karlovich, Alyssa Chapman, Brandie Fullmer, Ashley Hayes, Ruth Thornton, Nikitha Nair, Shahanawaz Jiwani, Lindsay Dutko, Kelly Benauer, Gloryvee Rivera, Corinne Camalier, John Carter, Suzanne Borgel, Tiffanie Miner, Chelsea McGlynn, Justine Mills, Shannon Uzelac, Tia Shearer, Lauren Hicks, Michelle Norris, Carley Border, Sergio Alcoser, Thomas Walsh, Michael Mullendore, Michelle Eugeni, Dianne Newton, Melinda G. Hollingshead, P. Mickey Williams, James H. Doroshow
Journal: Cancer Research (2023)

Abstract Introduction: Structural variants (SVs) are a unique class of mutations which have certain therapeutic implications for the tumor. Certain SVs, such as chromosomal aneuploidy, whole-genome doubling (WGD), have specific therapeutic implications. The underlying cellular processes present in the tumor are reflected in mutational signatures. Here, we describe the landscape of chromosomal aneuploidy, WGD and mutational signatures in the National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR) to facilitate the investigation of their roles in therapeutic responses of the preclinical models. Method: Chromosome arm-level aneuploidy was called by scoring at the individual arm level if &amp;gt;90% of the arm copy number (CN) was gained/lost based on whole-exome sequencing (WES) data. Aneuploidy score was defined as number of arms with aneuploidy. WGD was determined by derived allelic specific CN, purity and ploidy from tumor/normal matched samples and permutation test. Mutational signatures (COSMIC v3) including single base substitutions (SBS), doublet base substitutions (DBS), small insertions and deletions (ID) and CN signatures were derived using SigProfiler for specimens with somatic mutations and CNs. Results: A large fraction (85%) of patient-derived xenograft (PDX) models (N=755) have at least one arm -level aneuploidy. Certain chromosomes and arms (7, 8, 17p and 18) are more frequently aneuploid, which might be biased due to the overrepresentation of gastrointestinal cancer in the cohort. Histology specific differences were observed in the frequency of arm level aneuploidies. For example, synovial sarcoma (SYNS) and endometrioid carcinoma (UEC) have much lower level of aneuploidy than non-small cell lung cancer (NSCLC) or clear cell renal carcinoma (ccRCC) models. 61% of PDX models (N=277) have WGD, in which certain histologies have more WGD [NSCLC: 81%, head and neck squamous cell carcinomas (HNSCC): 71%] than others. Samples having WGD have a higher degree of aneuploidy and chromosomal instability. WGD and aneuploidy remain stable along the passages in 78% PDX models. Intra-model heterogeneity of WGD was observed due to lineage difference. Mutational signatures (SBS6,15,20) indicating concurrent DNA polymerase epsilon (POLE) mutation and defective DNA mismatch repair were highly enriched in microsatellite instability-high models (p&amp;lt;0.01, Fisher’s exact test). Among 30 PDX models where the patients had known platinum-based chemotherapy history, 40% of them had an identifiable platinum chemotherapy treatment signature (SBS31 or DBS5). Chromothripsis associated amplification signature (CN8) was enriched in models with WGD (p&amp;lt;0.05). Conclusion: We have characterized chromosomal aneuploidy, WGD and mutational signatures in NCI PDMR models. The models with SVs can be utilized in preclinical drug studies to understand their role in therapeutic response in patients. Citation Format: Li Chen, Biswajit Das, Ting-Chia Chang, Yvonne A. Evrard, Chris A. Karlovich, Alyssa Chapman, Brandie Fullmer, Ashley Hayes, Ruth Thornton, Nikitha Nair, Shahanawaz Jiwani, Lindsay Dutko, Kelly Benauer, Gloryvee Rivera, Corinne Camalier, John Carter, Suzanne Borgel, Tiffanie Miner, Chelsea McGlynn, Justine Mills, Shannon Uzelac, Tia Shearer, Lauren Hicks, Michelle Norris, Carley Border, Sergio Alcoser, Thomas Walsh, Michael Mullendore, Michelle Eugeni, Dianne Newton, Melinda G. Hollingshead, P. Mickey Williams, James H. Doroshow. Chromosomal aneuploidy, whole-genome doubling and mutational signatures in NCI PDMR models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6072.